Several approaches were utilized to identify drugs to block human immunodeficiency virus type 1 (HIV-1) replication in cell culture. Our studies show that palmitoil analogs of foscarnet can inhibit HIV reverse transcriptase and may be useful in the passage of the drug through the blood brain barrier. Chemically modified antisense oligonucleotides have been found to inhibit HIV replication in low concentration and without any toxic effect in cell culture.